CD44--HYALURONIC ACID BINDING AND LYMPHOCYTE MIGRATION

CD44--透明质酸结合和淋巴细胞迁移

• 批准号: 2066604
• 负责人: ROBERT A HYMAN
• 金额: $ 24.44万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-05-01 至 1996-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2066604
• 关键词: CD antigens; athymic mouse; cell adhesion; cell migration; chemical binding; clone cells; cytoskeleton; flow cytometry; hyaluronate; laboratory mouse; lymphocyte; monoclonal antibody; protein isoforms; protein structure

Directed lymphocyte migration requires the interaction of specific receptors, present on the lymphocyte cell surface, with ligands present on the surface of other cells or the extracellular matrix. The overall objective of this proposal is to understand how thymus-derived lymphocytes and their progenitors interact with the extracellular matrix. CD44 is a cell-surface molecule that is expressed on the earliest T- lymphocyte progenitors, on memory T-lymphocytes, and on certain lymphoid tumor cells that exhibit metastatic behavior. Several lines of evidence indicate that CD44 mediates binding to extracellular matrix components. Hyaluronic acid (HA) is one ligand for CD44. Although most normal hematopoietic cells express a CD44 isoform which potentially binds hyaluronic acid, most hematopoietic cells that express this CD44 isoform do not bind hyaluronic acid. This result implies that whether this CD44 isoform binds hyaluronic acid only under very specific conditions and under strict cellular control. The specific objective of this proposal is to determine the factors that determine whether the CD44 isoform on hematopoietic cells binds HA or not. This work has implications for understanding normal lymphocyte development, mechanisms of inflammation and lymphocyte migration in disease states, and the mechanisms underlying tumor cell metastasis. To accomplish the specific objective, we propose to: 1) Determine structural features of the CD44 molecule that are required for HA binding. 2) Determine how some CD44-specific monoclonal antibodies enhance the binding of HA. 3) Investigate the role of the cytoskeleton in binding HA and in the enhancement of HA-binding by CD44-specific antibodies. 4) Determine why some cell lines cannot be induced to bind HA by CD44- specific antibodies. 5) Investigate consequences of the activation of HA binding by CD44- specific antibodies on lymphocyte adhesion to epithelial cells and on thymocyte progenitor migration in vivo.

淋巴细胞的定向迁移需要特定的相互作用 受体存在于淋巴细胞表面，配体存在于 其他细胞或细胞外基质的表面。 整体 该提案的目的是了解胸腺来源的淋巴细胞如何 它们的祖细胞与细胞外基质相互作用。 CD44 是一种细胞表面分子，表达于最早的 T- 淋巴细胞祖细胞、记忆 T 淋巴细胞和某些淋巴细胞 表现出转移行为的肿瘤细胞。 几行证据 表明 CD44 介导与细胞外基质成分的结合。 透明质酸 (HA) 是 CD44 的一种配体。 虽然最正常 造血细胞表达 CD44 亚型，可能结合 透明质酸，大多数表达这种 CD44 亚型的造血细胞 不结合透明质酸。 这个结果意味着这个CD44是否 同种型仅在非常特定的条件下与透明质酸结合 严格的细胞控制。 该提案的具体目标是 确定决定 CD44 亚型是否存在的因素 造血细胞是否结合HA。 这项工作的意义在于 了解正常淋巴细胞的发育、炎症机制和 疾病状态下的淋巴细胞迁移以及肿瘤的机制 细胞转移。 为实现具体目标，我们建议： 1) 确定 CD44 分子所需的结构特征 HA 结合。 2) 确定一些 CD44 特异性单克隆抗体如何增强 HA 的结合。 3) 研究细胞骨架在结合HA和在 CD44 特异性抗体增强 HA 结合。 4) 确定为什么某些细胞系不能被CD44-诱导结合HA 特异性抗体。 5) 研究 CD44-HA 结合激活的后果 淋巴细胞与上皮细胞粘附的特异性抗体 胸腺细胞祖细胞在体内迁移。